Advanced glycation end‐products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor‐induced ICAM‐1 expression: inhibitory effect of antioxidants

Accumulating evidence indicates a role for advanced glycation end‐products (AGEs) in the development of diabetic retinopathy. In the present study, we examined the in vitro effect of AGEs on human monocyte adhesion to bovine retinal endothelial cells (BRECs) and the molecular mechanisms involved in this effect. Treatment of cultured BRECs with AGEs led to a significant increase in monocyte adhesion and intercellular cell adhesion molecule‐1 (ICAM‐1) expression. These effects were inhibited by antioxidants including gliclazide and vitamins C and E. On the basis of the stimulatory effect of AGEs on vascular endothelial growth factor (VEGF) secretion by retinal endothelial cells, the role of this growth factor as mediator of AGE‐induced monocyte adhesion to BRECs was next investigated. Incubation of BRECs with VEGF increased monocyte adhesion to these cells and enhanced ICAM‐1 expression. Treatment of BRECs with an anti‐VEGF antibody abrogated AGE‐induced monocyte adhesion and ICAM‐1 expression. Finally, incubation of BRECs with protein kinase C (PKC) and nuclear factor (NF)‐κB inhibitors suppressed monocyte adhesion and ICAM‐1 expression elicited by AGEs and VEGF. Taken together, these data indicate that AGEs increase monocyte adhesion to BRECs and that this effect is mediated through VEGF‐induced ICAM‐1 expression. They also demonstrate that this effect is oxidative stress‐sensitive and involves PKC and NF‐κB‐dependent signaling pathways.

[1]  R. Bucala,et al.  Advanced glycation end products increase retinal vascular endothelial growth factor expression. , 1998, The Journal of clinical investigation.

[2]  Bernd Kirchhof,et al.  Nonsteroidal anti‐inflammatory drugs prevent early diabetic retinopathy via TNF‐α suppression , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  Y. Ogura,et al.  Role of leukocytes in diabetic microcirculatory disturbances. , 1997, Microvascular research.

[4]  J. Williamson,et al.  Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C , 2001, Microcirculation.

[5]  K. Miyarnoto.  Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition , 1999 .

[6]  Hyung Jin Kim,et al.  Vascular Endothelial Growth Factor Expression of Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and E-selectin through Nuclear Factor-κB Activation in Endothelial Cells* , 2001, The Journal of Biological Chemistry.

[7]  M. Castresana,et al.  Reactive oxygen and NF-kappaB in VEGF-induced migration of human vascular smooth muscle cells. , 2001, Biochemical and biophysical research communications.

[8]  K. Ikeda,et al.  The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas , 1997, Diabetologia.

[9]  R. Busse,et al.  Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. , 1999, Diabetes.

[10]  K Miyamoto,et al.  Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). , 2000, The American journal of pathology.

[11]  H. Tritschler,et al.  α-Lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products , 1999 .

[12]  Chad Johnson,et al.  Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. , 2002, Circulation research.

[13]  R. de Caterina,et al.  Advanced Glycation End Products Activate Endothelium Through Signal-Transduction Receptor RAGE: A Mechanism for Amplification of Inflammatory Responses , 2002, Circulation.

[14]  F. Borek.  Journal of Leukocyte Biology , 2006, Journal of Leukocyte Biology.

[15]  P. Wiedemann,et al.  Advanced glycation end products induce choroidal endothelial cell proliferation, matrix metalloproteinase-2 and VEGF upregulation in vitro , 2002, Graefe's Archive for Clinical and Experimental Ophthalmology.

[16]  K Miyamoto,et al.  Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. , 2000, Investigative ophthalmology & visual science.

[17]  Wei-jian Zhang,et al.  α‐Lipoic acid inhibits TNF‐a‐induced NF‐κB activation and adhesion molecule expression in human aortic endothelial cells , 2001 .

[18]  H. Lum,et al.  Oxidant stress and endothelial cell dysfunction. , 2001, American journal of physiology. Cell physiology.

[19]  W. Gonzalez,et al.  Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[20]  A. Desfaits,et al.  Gliclazide reduces the induction of human monocyte adhesion to endothelial cells by glycated albumin , 1999, Diabetes, obesity & metabolism.

[21]  J. Williamson,et al.  Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. , 2001 .

[22]  Z. Makita,et al.  Increased Levels of Vascular Endothelial Growth Factor and Advanced Glycation End Products in Aqueous Humor of Patients With Diabetic Retinopathy , 2001, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[23]  L. Packer,et al.  Gliclazide scavenges hydroxyl, superoxide and nitric oxide radicals: an ESR study. , 1997, Research communications in molecular pathology and pharmacology.

[24]  L. Aiello,et al.  Hypoxic regulation of vascular endothelial growth factor in retinal cells. , 1995, Archives of ophthalmology.

[25]  L. Aiello,et al.  Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K Miyamoto,et al.  In vivo demonstration of increased leukocyte entrapment in retinal microcirculation of diabetic rats. , 1998, Investigative ophthalmology & visual science.

[27]  K. Kawasaki,et al.  Upregulation of Retinal Vascular Endothelial Growth Factor mRNAs in Spontaneously Diabetic Rats without Ophthalmoscopic Retinopathy , 1998, Ophthalmic Research.

[28]  J. Mamputu,et al.  Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide , 2004, Diabetes, obesity & metabolism.

[29]  A. Desfaits,et al.  Gliclazide decreases cell-mediated low-density lipoprotein (LDL) oxidation and reduces monocyte adhesion to endothelial cells induced by oxidatively modified LDL. , 1997, Metabolism: clinical and experimental.

[30]  Alan W. Stitt,et al.  The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. , 2002, Diabetes.

[31]  D. Faller,et al.  Spontaneous aggregation as a mechanism for human monocyte purification. , 1986, Cellular Immunology.

[32]  A. Iguchi,et al.  Effects of gliclazide on low-density lipoprotein oxidizability and atherosclerosis in cholesterol-fed rabbits. , 2000, Journal of atherosclerosis and thrombosis.

[33]  J. Mamputu,et al.  Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor expression in retinal endothelial cells. Inhibitory effect of gliclazide. , 2002, Journal of diabetes and its complications.

[34]  S. Bursell,et al.  Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. , 2003, Diabetes.

[35]  N. Nakamura,et al.  Advanced glycation end products induce expression of vascular endothelial growth factor by retinal Muller cells. , 1997, Biochemical and biophysical research communications.

[36]  P. Bath,et al.  Monocyte-lymphocyte discrimination in a new microtitre-based adhesion assay. , 1989, Journal of immunological methods.

[37]  B Kirchhof,et al.  Leukocyte-mediated endothelial cell injury and death in the diabetic retina. , 2001, The American journal of pathology.

[38]  K Miyamoto,et al.  Pathogenetic potential of leukocytes in diabetic retinopathy. , 1999, Seminars in ophthalmology.

[39]  R. O’Brien,et al.  In vitro and in vivo antioxidant properties of gliclazide. , 2000, Journal of diabetes and its complications.

[40]  Bernd Kirchhof,et al.  Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. , 2002, The American journal of pathology.

[41]  C. Kunsch,et al.  Oxidative stress as a regulator of gene expression in the vasculature. , 1999, Circulation research.

[42]  K Miyamoto,et al.  VEGF increases retinal vascular ICAM-1 expression in vivo. , 1999, Investigative ophthalmology & visual science.

[43]  Alan W. Stitt,et al.  Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats. , 2000, Molecular cell biology research communications : MCBRC.

[44]  A. Kumagai,et al.  Enhancement of glucose transport by vascular endothelial growth factor in retinal endothelial cells. , 2000, Investigative ophthalmology & visual science.

[45]  G. Romeo,et al.  Increased retinal endothelial cell monolayer permeability induced by the diabetic milieu: role of advanced non‐enzymatic glycation and polyol pathway activation , 2001, Diabetes/metabolism research and reviews.

[46]  R. Bucala,et al.  Immunochemical detection of advanced glycosylation end products in vivo. , 1992, The Journal of biological chemistry.